Process for the preparation of an enantiomerically enriched thio compound

ABSTRACT

The invention relates to a process for the preparation of an enantiomerically enriched compound of formula (1) or a salt thereof, in which R 1  and R 2  each independently represent an (hetero)alkyl or (hetero)aryl group, wherein R 1 —C(O)—SH or a salt thereof, with R 1  as defined above, is reacted with R 2 —C(C═CH 2 )—C(O)OH with R 2  as defined above, wherein the reaction takes place in the presence of catalyst is an enantiomerically enriched Lewis acid containing a transition metal chosen from the group of Ti, Zr and Hf or a combination thereof and at least one enantiomerically enriched ligand, and in the presence of an alkali metal ion, an alkaline earth metal ion or an ammonium ion.

The invention relates to a process for the preparation of anenantiomerically enriched thio compound of formula 1

or a salt thereof, wherein R¹ and R² each independently represent a(hetero)alkyl or (hetero)aryl group, wherein a thio compound of formula2

with R¹ as defined above, is reacted with an alkene of formula 3

or a salt thereof, with R² as defined above.

Such a process is known from JP-A-9278746, which discloses thepreparation of enantiomerically enriched 3-thioacyl-2-aralkyl propionicacid esters by contacting a thioacid with a 2-aralkyl acrylic acid esterin the presence of a cinchona alkaloid or a cinchona alkaloid whose OHis esterified.

The aim of the invention is to provide a commercially attractivealternative process comprising the preparation of an enantiomericallyenriched compound of formula 1 by asymmetric catalysis. Such compoundsare for instance used in the preparation of pharmaceuticals. This isachieved according to the invention by performing the reaction in thepresence of an enantiomerically enriched Lewis acid containing atransition metal chosen from the group of Ti, Zr and Hf or a combinationthereof and at least one enantiomerically enriched ligand, and in thepresence of an alkali metal ion, an alkaline earth metal ion or anammonium ion.

It is surprising that such a process results in the formation of anenantiomerically enriched product.

The terms Lewis acid and ligand are commonly known in the art anddefined in for example “Advanced Inorganic Chemistry”, F. A. Cotton andG. Wilkinson, John Wiley & Sons, 5^(th) ed., 1988, p. 35-36.

In the catalyst used in the process according to the invention thetransition metal chosen from the group of Ti, Zr and Hf is preferablypresent as M(IV), in which M=Ti, Zr or Hf. As a source for thetransition metal any salt or complex of the transition metal may beused. Examples of suitable salts or complexes are Ti halogenides, forexample TiCl₄, and Ti alkoxides, for example Ti(OC₂H₅)₄, Ti(OCH(CH₃)₂)₄,Ti(O(CH₂)₃CH₃)₄ and Ti(OCH(C₂H₅)(C₄H₉))₄. The catalyst can suitably beprepared starting form a transition metal complex containing achiralligands, many of which are readily available and relatively cheap. Ifsuch starting materials are used it may be desirable to remove at leastpart of the achiral ligands before said catalyst is applied in theprocess according to the invention to avoid competition between suchachiral ligands and the enantiomerically enriched ligand for binding tothe transition metal and to avoid the formation of an achiral Lewis acidwhich may have an adverse effect on the process. A broad range ofseparation techniques may be used to remove said ligands, for exampledistillation and extraction.

Preferably the catalyst contains Ti. It has been found that catalystscontaining Ti and an enantiomerically enriched ligand possesses both arelatively high enantioselectivity and a high catalytic activity.

The amount of transition metal used can vary within wide ranges and isdependent on for instance the type of transition metal andenantiomerically enriched ligand, the reactants and the reactionconditions, for example the temperature, the concentration of thetransition metal and the enantiomerically enriched ligand and thereactants and the type of solvent. Preferably 0.5-200 mol % oftransition metal is used based on the amount of R²—C(═CH₂)—COOH or asalt thereof, more preferably 1-100 mol %, most preferably 2-40 mol %.

The enantiomerically enriched Lewis acid contains at least oneenantiomerically enriched ligand with an e.e. of >90%, preferably >95%,more preferably >98%. A wide range of such ligands may be used. Examplesof suitable enantiomerically enriched ligands are (derivatives onenantiomerically enriched alcohols. Preferably an enantiomericallyenriched diol is present as the ligand, more preferably anenantiomerically enriched tartaric acid derivative, most preferably anenantiomerically enriched tartaric acid ester with formulaR³OC(O)—CH₂OH—CH₂OH—C(O)OR⁴, R³ and R⁴ each independently representing a(hetero)alkyl or (hetero)aryl group having 1-50 carbon atoms.Enantiomerically enriched tartaric acid esters are commerciallyavailable or can relatively easily be synthesised. Examples of suitableenantiomerically enriched tartaric acid esters are for instanceenantiomerically enriched diethyl tartrate, enantiomerically enricheddi-iso-propyl tartrate, enantiomerically enriched di-iso-propoxyethyltartrate, enantiomerically enriched di-2,2,2-trichloroethyl tartrate andenantiomerically enriched di-4-benzyloxybutyl tartrate.

The amount of enantiomerically enriched ligand relative to the amount oftransition metal ion is not particularly critical. Preferably anapproximately stoichiometric amount of enantiomerically enriched ligandis used based on the amount and valency of the transition metal ion. Forexample, if M(IV) is used in combination with a monodentate ligand, theratio enantiomerically enriched ligand: M(IV) is preferably between 3:1and 5:1, more preferably between 3.5:1 and 4.5:1, most preferablybetween 3.8:1 and 4.2:1, while in the case of a bidentate ligand, theratio enantiomerically enriched ligand: M(IV) is preferably between1.5:1 and 2.5:1, more preferably between 1.75:1 and 2.25:1, mostpreferably between 1.9:1 and 2.1:1.

The process according to the invention is carried out in the presence ofan alkali metal ion, an alkaline earth metal ion or an ammonium ion,which may be introduced to the reaction mixture in various ways, forexample by adding as a salt, preferably as a salt of one of thereagents, or by using a “solid carrier”, for example an ion exchangeresin, containing the ion. Preferably Na⁺ or Li⁺ are used, morepreferably a Na or Li salt of one of the reagents. Herein reagent refersto either a thio compound according to formula 2 or an alkene accordingto formula 3.

Preferably between 0.1 and 50 mol % of alkali metal ion, alkaline earthmetal ion or ammonium ion is used based on the amount of transitionmetal.

R¹ and R² each independently represent a (hetero)alkyl or (hetero)arylgroup. Suitable choices for R¹ and R² are an optionally substituted(hetero)alkyl group, optionally containing for instance one or more N, Oor S atoms, with for example 1 to 50 C atoms, for example a methyl,ethyl, propyl, butyl, tertiary butyl, benzyl group or an optionallysubstituted (hetero)aryl group with for example 1 to 50 C atoms, forexample a phenyl, naftyl, pyridyl, pyrrolyl, chinolyl, isochinolyl,furyl, thienyl, benzofuryl, indenyl, pyrimidinyl, pyrazolyl orimidazolyl group. The (hetero)alkyl or (hetero)aryl group of R¹ or R² isoptionally substituted with one or more substituents which are inertunder the chosen reaction conditions. Suitable examples of suchsubstituents are an (hetero)alkyl group with for example 1 to 20 Catoms, for example a methyl, ethyl, isobutyl or trifluoromethyl group;an alkenyl group with for example 2 to 20 C atoms, an alkoxy group withfor example 1 to 20 C atoms, a (hetero)aryl group with for example 1 to20 C atoms, an aryloxy group with for example 1 to 20 C atoms, an aminogroup, a hydroxy group or a halogen.

Particularly suitable examples of R¹ are a methyl group, a tertiarybutyl group, a cyclohexyl group and a phenyl group.

Particularly suitable examples of R² are a methyl group; a substitutedor unsubstituted benzyl group, for example a benzyl group, a4-chlorobenzyl group, a 4-bromobenzyl group and a 4-methoxybenzyl group;a 1-naphtalylmethyl group; a 2-naphtalylmethyl group; a1,1′-biphenylmethyl group; a substituted or unsubstituted aryloxyalkylgroup, for example a substituted or unsubstituted phenoxyalkyl group,for example a 3-(4-ethylphenoxy)propyl group, a3-(4-benzoylphenoxy)propyl group, a 3-(4-methylphenoxy)propyl group, a3-(3-ethylphenoxy)propyl group, a 3-(4-(phenylmethyl)phenoxy)propylgroup, a 4-(3-cyanophenoxy)butyl group, a 4-(4-phenoxyphenoxy)butylgroup, a 4-(2,6-dimethylphenoxyl)butyl group, a4-(4-n-propoxyphenoxy)butyl group, a 4-(4-iodophenoxy)butyl group, a4-[4-(acetylamino)phenoxy]butyl group, a4-[4-(phenoxymethyl)phenoxy]butyl group, a4-[4-(trifluoromethyl)phenoxy]butyl group, a 4-(3-ethylphenoxy)butylgroup, a 4-(3-chlorophenoxy)butyl group, a5-[4-(phenoxymethyl)phenoxy]pentyl group, a 5-(4-ethoxyphenoxy)pentylgroup and a 6-phenylhexyl group; a substituted or unsubstitutedphenylcarbonylmethyl group, for example a (4-bromophenyl)carbonylmethylgroup, a (3,4-dimethylphenyl)carbonylmethyl group, a(2,4-dimethylphenyl)carbonylmethyl group, a[4-(4-chlorophenoxy)phenyl]carbonylmethyl group, a(4-phenoxyphenyl)carbonylmethyl group, a (4-methoxyphenyl)carbonylmethylgroup, a (4-isopropoxyphenyl)carbonylmethyl group, a(4-methylphenyl)carbonylmethyl group, a (4-bromophenyl)carbonylmethylgroup, a (4-chlorophenyl)carbonylmethyl group and a(4-fluorophenyl)carbonylmethyl group; a substituted or unsubstitutedpyridylmethyl group, for example a (2-aminopyridin-5-yl)methyl group, a[2-(t-butoxycarbonylamino)pyridin-5-yl]methyl group and a[2-(t-butoxycarbonylamino)-6-methyl-pyridin-5-yl]methyl group.

The compound of formula (3) may be used as a carboxylic acid or acarboxylic acid salt, for example an (alkali or alkaline earth) metal orammonium salt. Preferably a carboxylic acid or a Na, K, Li salt thereofare used, more preferably a carboxylic acid is used. The compound offormula (3) may be formed in situ using a precursor that is capable offorming such compound under the applied reaction conditions.

The process according to the invention is particularly suitable for theproduction of carboxylic acids according to formula 1 in which R¹represents a methyl group and R² represents a benzyl or a methyl group.

The molar ratio between the reactants R¹—C(O)—SH and R²—C(═CH₂)—C(O)OHor a salt thereof is not particularly critical and may vary between forexample 10:1 and 1:10, preferably between 5:1 and 1:5, more preferablybetween 2.5:1 and 1:2.5, most preferably between 1.6:1 and 1:1.1.

The temperature at which the process is performed is not particularlycritical and can easily be optimised by the skilled person. Usually areaction temperature between 0 and 150° C. is applied, preferablybetween 20 and 110° C., more preferably between 30 and 80° C.Surprisingly it was found that in some cases at a relatively hightemperature both the output and enantioselectivity were higher.

The process according to the invention preferably is carried out in thepresence of a solvent. In the case of one or more liquid reagents theprocess can also be carried out in the absence of a solvent. Preferablya solvent is applied. A wide range of organic solvents can be used inthe process, as long as they are inert under the chosen reactionconditions, for example optionally substituted aliphatic hydrocarbons,for instance n-hexane, n-heptane, dichloromethane, 1,2-dichloroethaneand trichloromethane, optionally substituted (hetero)aromatichydrocarbons, for instance toluene or N-methyl pyrrolidon, optionallysubstituted ethers, for instance methyl t-butyl ether ortetrahydrofuran, optionally substituted carboxylic acids, for instanceacetic acid, optionally substituted esters, for instance ethyl acetate,optionally substituted nitrites, for instance acetonitrile or optionallysubstituted ketones, for instance methyl isobutyl ketone. Some of thesesolvents were found to have a positive effect on the selectivity of thereaction and thus on the ee of the product, the effect depending on e.g.the reactants and catalyst applied. Preferably an optionally substitutedalifatic or aromatic hydrocarbon or an optionally substituted ether isused as the solvent, more preferably toluene.

The enantiomerically enriched thio compound prepared by the methodaccording to the invention can be isolated using various methods.Suitable methods are, for instance, isolation as the compound as such,for example by crystallisation, conversion of the compound with anachiral base into a salt and subsequent crystallisation of said salt orreacting the compound with an enantiomerically enriched base andsubsequent crystallisation of the formed diastereomeric salt.

In one embodiment of the invention the enantiomerically enriched thiocompound prepared by the method according to the invention is isolatedby contacting with an amine, followed by crystallisation of the formedsalt of the enantiomerically enriched thio compound and the amine andconversion of the salt into the enantiomerically enriched thio compoundand the amine using methods known per se. It was found that by applyingsuch procedure the transition metal can be separated from theenantiomerically enriched thio compound and that the enantiomericallyenriched thio compound can be obtained in high purity. Different typesof amines can be used, both aliphatic and aromatic amines, the optimalchoice of the amine depending on the compound to be isolated. Forexample, it has been found that (S)-3-thioacetyl-2-benzylpropionic acidcan suitably isolated in the presence of cyclohexylamine.

The invention will now be explained in more detail with reference to thefollowing examples, without however being limited thereto.

EXAMPLES Example I Preparation of the Catalyst

To 200 ml of toluene, 18.72 g (66 mmol) of titanium tetra-iso-propoxideand 28.32 g (137 mmol) of L-diethyl tartrate were added at 20° C. undernitrogen atmosphere. The mixture was stirred for 48 hours at 20° C.After removal of the volatiles by distillation at reduced pressure (10mg Hg) and elevated temperature (60° C.) an oil was obtained, which wasdissolved in toluene to a total volume of 200 ml. The resulting catalystsolution, containing 0.33 mol Ti per liter, was used in examples II-XIV.

Example II Preparation of Enantiomerically Enriched(S)-3-thioacetyl-2-benzyl propionic acid

To 90 ml of toluene, 110 mg (1 mmol) of sodium methacrylate and 3.24 g(20 mmol) of 2-benzylacrylic acid were added at 70° C. The resultingmixture was stirred for 15 minutes, followed by the addition of 8.5 mlof the catalyst solution prepared in example 1 (2.8 mmol Ti-catalyst) at70° C. The mixture was stirred for an additional 15 minutes at 70° C.1.56 ml (22.7 mmol) of thioacetic acid was dosed to the reaction mixtureat 70° C. within 15 minutes. The reaction mixture was stirred for 1 hourat 70° C. to complete the conversion. The e.e. of(S)-3thioacetyl-2-benzylpropionic acid in the reaction mixture, asdetermined by HPLC, was 44%.

Example III Preparation of Enantiomerically Enriched(S)-3-thioacetyl-2-benzyl propionic acid

To 700 ml toluene, 4.93 g (26.8 mmol) of sodium 2-benzylacrylate and24.0 g (148 mmol) of 2-benzylacrylic acid were added at 70° C. Theresulting mixture was stirred for 15 minutes to dissolve most of the2-benzylacrylic acid. 200 ml of the catalyst solution prepared inexample 1 (66 mmol Ti-catalyst) was added at 70° C. The mixture wasstirred for an additional 15 minutes at 70° C. A solution of 18 ml ofthioacetic acid (262 mmol) in 50 ml toluene was dosed to the reactionmixture at 70° C. within 30 minutes. The reaction mixture was stirredfor 3 hours at 70° C. to complete the conversion. The e.e. ofS-3-thioacetyl-2-benzyl propionic acid in the reaction mixture, asdetermined by HPLC, was 50%. The reaction mixture was subsequentlycooled to 35° C., after which the excess of thioacetic acid was removedby distillation at reduced pressure at 35° C. until the total weight ofthe residue was 350 gram. After further cooling the mixture to 25° C.,300 ml of toluene was added, followed by the addition of 20 grams ofcyclohexylamine within 30 minutes, during which the product started tocrystallise. The heterogeneous mixture was stirred at 25° C. for anadditional 2 hours. The solid was collected by filtration and washedwith 250 ml of toluene. The wet cake was air dried at room temperature,yielding 46.4 g of the salt of (S)-3-thioacetyl-2-benzyl propionic acidand cyclohexylamine in a purity of >98%, according to HPLC. The e.e. ofthe (S)-3-thioacetyl-2-benzyl propionic acid in the salt was 55%, whichis higher than the e.e. before contacting with cyclohexylamine. Theoverall yield based on the amount of sodium 2-benzylacrylate and2-benzylacrylic acid was 78%.

Example IV Preparation of Enantiomerically Enriched(S)-3-thioacetyl-2-methyl propionic acid

To 95 ml of toluene, 40.1 mg (0.37 mmol) of sodium methacrylate and 1.72g (20 mmol) of methacrylic acid were added at 70° C. The resultingmixture was stirred for 15 minutes. 3 ml of the catalyst solutionprepared in example 1 (1 mmol of Ti-catalyst) was added at 70° C. Afteraddition of the catalyst the mixture was stirred for an additional 15minutes at 70° C. 1.56 ml (22.7 mmol) of thioacetic acid was dosed tothe reaction mixture at 70° C. within 15 minutes. The reaction mixturewas stirred for 1 hour at 70° C. to complete the conversion. The e.e. of(S)-3-thioacetyl-2-methylpropionic acid in the reaction mixture, asdetermined by HPLC, was 44%.

Example V Preparation of Enantiomerically Enriched(S)-3-thioacetyl-2-methyl propionic acid

To 95 ml of toluene, 82 mg (0.76 mmol) of sodium methacrylate and 1.72 g(20 mmol) of methacrylic acid were added at 70° C. The resulting mixturewas stirred for 15 minutes. 6 ml of the catalyst solution prepared inexample 1 (2 mmol of Ti-catalyst) was added at 70° C. After addition ofthe catalyst the mixture was stirred for an additional 15 minutes at 70°C. 1.56 ml (22.7 mmol) of thioacetic acid was dosed to the reactionmixture at 70° C. within 15 minutes. The reaction mixture was stirredfor 1 hour at 70° C. for completion of the conversion. The e.e. of(S)-3-thioacetyl-2-methylpropionic acid in the reaction mixture, asdetermined by HPLC, was 53%.

Example VI Preparation of Enantiomerically Enriched(S)-3-thioacetyl-2-methyl propionic acid

To 95 ml of toluene, 156 mg (1.44 mmol) of sodium methacrylate and 1.729 (20 mmol) of methacrylic acid were added at 70° C. The resultingmixture was stirred for 15 minutes. 12 ml of the catalyst solutionprepared in example 1 (4 mmol Ti-catalyst) was added at 70° C. Afteraddition of the catalyst the mixture was stirred for an additional 15minutes at 70° C. 1.56 ml (22.7 mmol) of thioacetic acid was dosed tothe reaction mixture at 70° C. within 15 minutes. The reaction mixturewas stirred for 1 hour at 70° C. to complete the conversion. The e.e. of(S)-3-thioacetyl-2-methylpropionic acid in the reaction mixture, asdetermined by HPLC, was 48%.

Example VII Preparation of Enantiomerically Enriched(S)-2-(acetylthiomethyl)butyric acid

To 100 ml of toluene, 90 mg (0.83 mmol) of sodium methacrylate and 2.00g (20 mmol) of 2-ethylacrylic acid were added at 70° C. The resultingmixture was stirred for 15 minutes. 8.5 ml of the catalyst solutionprepared in example 1 (2.8 mmol Ti-catalyst) was added at 70° C. Afteraddition of the catalyst the mixture was stirred for an additional 15minutes at 70° C. 1.56 ml (22.7 mmol) of thioacetic acid was dosed tothe reaction mixture at 70° C. within 15 minutes. The reaction mixturewas stirred for 1 hour at 70° C. to complete the conversion. The e.e. of(S)-2-(acetylthiomethyl)butyric acid in the reaction mixture, asdetermined by HPLC, was 63%.

Example VII Preparation of Enantiomerically Enriched(S)-2-(acetylthiomethyl)hexanoic acid

To 100 ml of toluene, 104 mg (0.96 mmol) of sodium methacrylate and 2.75g (21.5 mmol) of 2-butylacrylic acid were added at 70° C. The resultingmixture was stirred for 15 minutes. 9 ml of the catalyst solutionprepared in example 1 (3 mmol Ti-catalyst) was added at 70° C. Afteraddition of the catalyst the mixture was stirred for an additional 15minutes at 70° C. 1.56 ml (22.7 mmol) of thioacetic acid was dosed tothe reaction mixture at 70° C. within 15 minutes. The reaction mixturewas stirred for 1 hour at 70° C. to complete the conversion. The e.e. of(S)-2-(acetylthiomethyl)hexanoic acid in the reaction mixture, asdetermined by HPLC, was 69%.

Example IX Preparation of Enantiomerically Enriched(S)-3-thioacetyl-2-methylproprionic acid

To 100 ml of toluene, 180 mg (1.67 mmol) of sodium methacrylate and 8.60g (100 mmol) of methacrylic acid were added at 23° C. The resultingmixture was stirred for 15 minutes at 23° C. 15 ml of the catalystsolution prepared in example 1 was added at 23° C., followed by stirringthe mixture for an additional 15 minutes at 23° C. 7.6 g (100 mmol) ofthioacetic acid was added in 15 minutes and the mixture was stirred for72 hours at 23° C. The conversion was >90% according to HPLC. The e.e.,as determined by HPLC, was 23%.

Example X Preparation of Enantiomerically Enriched(S)-3-thiobenzoyl-2-methylpropionic acid

To 100 ml of toluene, 180 mg (1.67 mmol) of sodium methacrylate and 8.60g (100 mmol) of methacrylic acid were added at 70° C. The resultingmixture was stirred for 15 minutes at 70° C. 15 ml of the catalystsolution prepared in example 1 was added at 70° C., followed by stirringthe mixture for an additional 15 minutes at 70° C. A solution of 13.8 g(100 mmol) of thiobenzoic acid in 50 ml of toluene was added in 18minutes, after which the mixture was stirred for 3 hours at 70° C. Theconversion was >90% according to HPLC. The e.e., as determined by HPLC,was 35%.

Example XI Preparation of Enantiomerically Enriched(S)-3-thioacetyl-2-methylproprionic acid

To 100 ml of toluene, 180 mg (1.67 mmol) of sodium methacrylate and 8.60g (100 mmol) of methacrylic acid were added at 70° C. The resultingmixture was stirred for 15 minutes at 70° C. 15 ml of the catalystsolution prepared in example 1 was added at 70° C., followed by stirringthe mixture for an additional 15 minutes at 70° C. 7.6 g (100 mmol) ofthioacetic acid was added in 15 minutes and the mixture was stirred for3 hours at 70° C. The conversion was >90% according to HPLC. The e.e.,as determined by HPLC, was 45%.

Example XII Preparation of Enantiomerically Enriched(S)-3-thioacetyl-2-phenyl propionic acid

To 100 ml of toluene, 110 mg (1.0 mmol) of sodium methacrylate and 2.96g (20 mmol) of 2-phenylacrylic acid were added at 70° C. The resultingmixture was stirred for 15 minutes at 70° C. 9 ml of the catalystsolution prepared in example 1 was added at 70° C., followed bystrirring the mixture for an additional 15 minutes at 70° C. 1.52 gramsof thioacetic acid (20 mmol) was added in 15 minutes, after which themixture was stirred for 0.5 hours at 70° C. The e.e., as determined byHPLC, was 48%.

Example XIII Preparation of Enantiomerically Enriched(S)-3-thiobenzoyl-2-phenyl propionic acid

To 100 ml of toluene, 110 mg (1.0 mmol) of sodium methacrylate and 2.98g (20 mmol) of 2-phenylacrylic acid were added at 70° C. The resultingmixture was stirred for 15 minutes at 70° C. 9 ml of the catalystsolution prepared in example 1 was added at 70° C., followed by stirringthe mixture for an additional 15 minutes at 70° C. 2.60 g (20 mmol) ofthiobenzoic acid was added in 15 minutes, after which the mixture wasstirred for 0.5 hours at 70° C. The e.e., as determined by HPLC, was38%.

1. A process for the preparation of an enantiomerically enrichedcompound of formula 1

or a salt thereof, wherein R¹ and R² each independently represent alkyl,heteroalkyl, aryl or heteroaryl, which process comprises reacting acompound of formula 2

wherein R¹ is defined as above, with a compound of formula 3

or a salt thereof, wherein R² is defined as above, in the presence of anenantiomerically enriched Lewis acid containing a transition metalselected from the group consisting of Ti, Zr and Hf and a combinationthereof, at least one enantiomerically enriched ligand, and an alkalimetal ion, an alkaline earth metal ion or an ammonium ion.
 2. Theprocess of claim 1, wherein the transition metal is Ti.
 3. The processof claim 1, wherein the ligand is an enantiomerically enriched tartaricacid ester.
 4. The process of claim 1, wherein the alkali metal ion, thealkaline earth metal ion or the ammonium ion is Na⁺ or Li⁺.
 5. Theprocess of claim 1, wherein R¹ is methyl.
 6. The process of claim 1,wherein R² is methyl or benzyl.
 7. The process of claim 1, wherein themolar ratio between R¹—SH and R²—C(═CH₂)—C(O)OH in the reaction mixtureis between 2.5:1 and 1:2.5
 8. The process of claim 1, wherein theenantiomerically enriched compound of formula (2) has been isolated bycontacting said compound with an amine and crystallizing the saltformed.
 9. The process of claim 1, wherein the transition metal is Tiand the ligand is an enantiomerically enriched tartaric acid ester. 10.The process of claim 9, wherein R¹ is methyl and R² is methyl or benzyl.11. The process of claim 9, wherein the alkali metal ion, the alkalineearth metal ion or the ammonium ion is Na⁺ or Li⁺.